We have taken a functional genomic approach to ask what is different between nearby regions of electrically-mapped human neocortex removed surgically for the treatment of medically refractory epilepsy. We identified a small group of genes that are significantly induced at epileptic foci in almost all patients examined, regardless of underlying lesion. For the first time now, we have highly reliable molecular markers of epileptic neocortex that point to a specific signaling pathways and populations of neurons that characterize neocortical epileptic foci. While it is still not clear whether the induction of these genes are a consequence or a driving force of abnormally firing neurons, we found that the induction of many of these genes correlate precisely with the degree interictal spiking suggesting that the molecular pathways identified and interictal spiking are closely related. In this proposal, we will measure a group of quantitative parameters of interictal spiking from the neocortex of patients undergoing epilepsy surgery and relate these to the generation of seizures and the underlying gene expression and signaling pathways. These will be placed within the 3-dimensional structure of the human brain to ask further questions about the human brain's infoldings on human epilepsy. One long-term goal for this project is to develop an understanding of the clinical significance of interictal spiking to help guide future clinical decisions. Another goal is to understand the relationships between electrical activity with molecular and cellular pathways that will help us develop new, biologically-driven, diagnostics and therapeutics for human epilepsy. PUBLIC HEALTH RELEVANCE: Epilepsy is a common neurological disorder affecting up to 1% of the world's population. It is one of the least understood disorders that can develop after a wide range of brain insults. At present, there are no treatments to prevent epilepsy, and while existing medications reduce seizure frequency, they do not "cure" the disorder. It is possible to "cure" epilepsy by removing electrically-defined epileptic foci. Removal of these focal brain regions also presents an opportunity to discover the molecular and cellular basis of human epilepsy in a way that cannot be achieved in animal models. The improved methods we develop to measure spiking and the molecular and clinical correlates of interictal spiking will have great utility both for clinical management of patients with epilepsy and for the development of novel, targeted treatment and diagnostic strategies.